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Noncanonical Wnt11 inhibits hepatocellular carcinoma cell proliferation and migration
Takashi Toyama1, Han Chu Lee, Hironori Koga
1Liver Research Center, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
Abstract:
The canonical Wnt signaling is frequently activated due to overexpression and/or mutations in components of this pathway in hepatocellular carcinoma (HCC). However, the biological role of noncanonical Wnt-mediated signaling in HCC with respect to the signaling pathways involved and their physiologic function is unknown. Here, we report the role of Wnt11, a member of the noncanonical cascade, in hepatic oncogenesis. The expression levels of Wnt11 mRNA and protein were significantly downregulated in human HCC tumors compared with the adjacent uninvolved liver as measured by quantitative real-time reverse transcription-PCR and Western blot analysis. In human HCC cell lines, overexpression of Wnt11 activated protein kinase C signaling. Protein kinase C antagonized the canonical signaling through phosphorylation of beta-catenin and reduced T-cell factor-mediated transcriptional activity, resulting in a decrease of cell proliferation. Furthermore, ectopic expression of Wnt11 promotes RhoA/Rho kinase activation. We found that activated Rho kinase inhibited Rac1 to reduce cell motility and migration. These observations suggest a novel role for Wnt11 as a tumor suppressor during hepatocarcinogenesis because loss of expression promotes the malignant phenotype via both canonical and noncanonical Wnt signaling pathways.
Insights
Wnt11 acts as a tumor suppressor in liver cancer. Its downregulation promotes hepatocellular carcinoma (HCC) by activating both canonical and noncanonical Wnt pathways, increasing cell proliferation and migration.
Area of Science:
- Hepatocellular carcinoma (HCC) research
- Molecular oncology
- Signal transduction
Background:
- Canonical Wnt signaling is often hyperactivated in hepatocellular carcinoma (HCC).
- The role of noncanonical Wnt signaling, specifically Wnt11, in HCC oncogenesis remains largely uncharacterized.
- Understanding Wnt11's function is crucial for identifying novel therapeutic targets in liver cancer.
Purpose of the Study:
- To investigate the role of Wnt11 in hepatocellular carcinoma (HCC) development.
- To elucidate the specific noncanonical Wnt signaling pathways influenced by Wnt11 in HCC.
- To determine the functional consequences of Wnt11 expression or loss on HCC cell behavior.
Main Methods:
- Quantitative real-time reverse transcription-PCR and Western blot analysis to assess Wnt11 expression levels in HCC tumors and cell lines.
- Overexpression studies in HCC cell lines to analyze the effects of Wnt11 on protein kinase C (PKC) and RhoA/Rho kinase (ROCK) signaling.
- Assessment of beta-catenin phosphorylation, T-cell factor (TCF)-mediated transcriptional activity, cell proliferation, cell motility, and migration.
Main Results:
- Wnt11 mRNA and protein expression were significantly downregulated in human HCC tissues compared to adjacent normal liver.
- Overexpression of Wnt11 in HCC cell lines activated PKC, leading to beta-catenin phosphorylation and reduced TCF activity, ultimately decreasing cell proliferation.
- Ectopic Wnt11 expression promoted RhoA/ROCK activation, which inhibited Rac1, thereby reducing cell motility and migration.
Conclusions:
- Wnt11 functions as a tumor suppressor in hepatocarcinogenesis.
- Loss of Wnt11 expression promotes the malignant phenotype in HCC through dysregulation of both canonical and noncanonical Wnt signaling pathways.
- Wnt11's tumor-suppressive role involves antagonizing canonical Wnt signaling via PKC and inhibiting cell migration through the RhoA/ROCK pathway.
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